The long-term objective of our laboratory is to identify novel molecular targets for cancer. Kras is one of the most frequently mutated oncogenes in human cancer. Kras mutations are prevalent in lung, pancreas and colon carcinomas. We previously used mouse-to-human gene expression comparisons to identify a gene expression signature specific to Kras mutation. We have now carried out a screen using shRNA to test the functional significance of this signature and identify potential transcriptional regulators. This screen has identified a role for the transcription factor Wt1 in Kras-driven oncogenesis. In Specific Aim 1 we will identify the mechanism linking Wt1 to oncogenic Kras signaling. Wt1is a gene with pleiotropic effects involving roles as both a tumor suppressor and oncogene. We will use rescue experiments to define the role of Wt1 isoforms in Kras-induced oncogenesis. In addition, we outline several approaches to identify the key signaling pathways that link Wt1 to Kras effectors. These experiments will be strengthened by the availability of a conditional Wt1 knock-out mouse that will be used in our studies. Despite an increasingly sophisticated understanding about the molecular underpinnings of cancer, specific therapies that target these molecular changes are limited. Using sophisticated functional genomic approaches, we have identified several potential novel regulators of Kras-driven oncogenesis in the lung. Here we focus on dissecting the molecular mechanisms of two of these novel regulators. An understanding of the molecular basis for a role of Wt1 in Kras-driven oncogenesis may identify novel pathways that would be amenable to therapeutic intervention.